AR056218A1 - PHARMACEUTICAL COMPOSITION OF RELEASE MAINTAINED COMPRESSED IMMEDIATE RELEASE AND ORALALLY ADMINISTRABLE COMPRESSED UNDERSTANDING A WATER SOLUBLE SLA D 8- (2,6-DIFLUOROPHENIL) -4- (4-FLUORO-2-METHYLPHENID) -2 - {[2-] -1- (HYDROXIMETHYL) ETHYL] AMINO} PIRID (2,3-D) PYRIMIDIN-7 (8H) -ONA; SUCH COMPOUNDS - Google Patents

Abstract

A pharmaceutical sustained release composition comprising as an active ingredient a water soluble salt of 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2 - {[2-hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [2,3-d] pyrimidin-7 (8H) -one. A pharmaceutical composition in the form of an orally administrable modified-release tablet comprising a water soluble salt of 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2 - {[2-hydroxy -1- (hydroxymethyl) ethyl] amino) pyrido [2,3- d] pyrimidin-7 (8H) -one. Preferably, the water soluble salt is the tosylate salt. In another embodiment the tablet provides a full-day therapeutic effect on a mammal when administered once a day. Pharmaceutical composition in the form of an orally administrable modified-release tablet comprising 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2- {[2-hydroxy-1- 4-methylbenzenesulfonate) (hydroxymethyl) -ethyl] amino} pyrido [2,3-d] pyrimidin-7 (8H) -one (tosylate salt). Formulation of a water soluble salt of 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2 - {[2-hydroxy-1- (hydroxymethyl) -ethyl] amino} pyrido [ 2,3-d] pyrimidin-7 (8H) -one in a hydrophilic matrix tablet. Preferably, the water soluble salt is the tosylate salt. Modified release composition comprising a water soluble salt of 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2 - {[2-hydroxy-1- (hydroxymethyl) -ethyl] amino) pyrido [2,3-d] pyrimidin-7 (8H) -one, which has sufficient hardness to withstand a high speed dredging operation, especially to resist erosion during application of a coating layer if necessary . The tosylate salt of 8- (2,6-difluorophenyl) -4- (4-fluoro-2- methylphenyl) -2 - {[2-hydroxy-1- (hydroxymethyl) -ethyl] amino} pyrido [2, 3-d] pyrimidin-7 (8H) -one; the pharmaceutical compositions comprising the tosylate salt and a pharmaceutically acceptable carrier or diluent, and its use to prepare a medicament for the treatment of a disease or disease mediated by the activity of p38 kinase or mediated by cytokines produced by the activity of the p38 kinase Polymorphic forms, Forms 1 to 4 of 8- (2,6-difluorophenyl) -4- (4-fluoro-2-methylphenyl) -2 - {[2- hydroxy-1- (hydroxymethyl) ethyl] amino} pyrido [23 -d] pyrimidin-7 (8H) -one tosylate, the pharmaceutical compositions comprising these polymorphic forms, alone or in combination or mixtures thereof, and a pharmaceutically acceptable carrier or diluent and the use of these polymorphic forms of the salt of tosylate to treat a disease or disease mediated by the activity of p38 kinase or mediated by cytokines produced by the activity of p38 kinase. Intermediates of Formula (2), where: R1 is independently selected from hydrogen, C (Z) N (R10 ') (CR10R20) vRb, C (Z) O (CR10R20) vRb, N (R10') C (Z) (CR10R20) vRb, N (R10 ') C (Z) N (R10') (CR10R20) vRb, or N (R10 ') OC (Z) (CR10R20) vRb; R1 'is independently selected in each case from hydrogen, halogen, C1-4 alkyl, halo-substituted C1-4 alkyl, cyano, nitro, (CR10R20) v'NRdRd', (CR10R20) v'C (O) R12, SR5 , S (O) R5, S (O) 2R5 or (CR10R20) v'OR13; R3 is independently selected from hydrogen, halogen, C1-4 alkyl, or halo substituted C1-4 alkyl; R4 and R14 are each independently selected in each case from hydrogen or C1-4 alkyl, or R4 and R14, together with the nitrogen to which they are attached form a 5- to 7-membered heterocyclic ring, where said ring optionally contains an additional heteroatom selected from NR9; R5 is independently selected in each case from hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or NR4R14, excluding SR5 moieties that are SNR4R14, S (O) 2R5 that are SO2H and S (O) R5 which are SOH; R9 is independently selected in each case from hydrogen or C1-4 alkyl; R 12 is independently selected in each case from a hydrogen moiety, C 1-4 alkyl, halo C 1-4 alkyl substituted, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocyclyl or heterocyclyl-C1-4 alkyl alkyl, and in which each of these residues excluding hydrogen, may be optionally substituted; R13 is independently selected in each case from a hydrogen moiety, C1-4 alkyl, halo C1-4 alkyl substituted, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocyclyl or heterocyclyl-C1-4 alkyl alkyl, and in which each of these residues, excluding hydrogen, may be optionally substituted; each of Rd and Rd 'is independently selected from a hydrogen moiety, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, and in which each of these moieties, excluding hydrogen, can be optionally substituted; or Rd and Rd ', together with the nitrogen to which they are attached, form an optionally substituted 5 to 6 membered heterocyclic ring, wherein said ring optionally contains a heteroatom more selected from oxygen, sulfur or NR9'; Rb is a hydrogen, C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-10 alkyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, heterocyclyl or heterocyclyl-C1-alkyl moiety -10, where all these residues, excluding hydrogen, may be optionally substituted; Rg is C1-10 alkyl, or aryl; m is 0 or an integer that has a value of 1, or 2; s is an integer that has a value of 1, 2, 3 or 4; and t is an integer that has a value of 1, 2, 3 or 4; v is 0 or an integer that has the value 1 or 2; v 'is independently selected in each case from 0 or an integer having a value of 1 or 2; Z is independently selected from oxygen or sulfur; R10 and R20 are independently selected from hydrogen or C1-4 alkyl; and R10 'is independently selected in each case of hydrogen or C1-4 alkyl. Process for manufacturing a compound of Formula (2) by cyclization of a compound of Formula (4), in which R1, R1 ', R3, syt are as described above for Formula (2), m is 0.1 or 2 and Rg is a C1-10 alkyl or aryl, with a condensing agent selected from Meldrum acid or malonic acid, in an organic solvent, and with a base to yield a compound of Formula (2). Decarboxylation process of a compound of Formula (2) with a thio acid, or a salt of a thio acid, to yield a compound of Formula (3), in which R1 is independently selected from hydrogen, C (Z) N (R10 ' ) (CR10R20) vRb. C (Z) O (CR10R20) vRb, N (R10 ') C (Z) (CR10R20) vRb, N (R10') C (Z) N (R10 ') (CR10R20) vRb, or N (R10') OC (Z) (CR10R20) vRb; R1 'is independently selected in each case from hydrogen, halogen, C1-4 alkyl, halo-substituted C1-4 alkyl, cyano, nitro, (CR10R20) v'NRdRd', (CR10R20) C (O) R12, SR5, S (O) R5, S (O) 2R5 or (CR10R20) OR13; R3 is independently selected from hydrogen, halogen, C1-4 alkyl, or halo substituted C1-4 alkyl; R4 and R14 are each independently selected in each case from hydrogen or C1-4 alkyl, or R4 and R14 together with the nitrogen to which they are attached form a 5- to 7-membered heterocyclic ring, wherein said ring optionally contains an additional heteroatom selected of NR9; R5 is independently selected in each case from hydrogen, C1-4 alkyl C2-4 alkenyl, C2-4 alkynyl or NR4R14, excluding SR5 moieties that are SNR4R14, S (O) 2R5 that are SO2H and S (O) R5 that are SOH; R9 is independently selected in each case from hydrogen or C1-4 alkyl; R 12 is independently selected in each case from a hydrogen moiety, C 1-4 alkyl, halo C 1-4 alkyl substituted, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkyl-C 1-4 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl; heteroaryl, heteroaryl-C1-4alkyl, heterocyclyl or heterocyclyl-C1-4alkyl, and in which each of these moieties, excluding hydrogen, may be optionally substituted; R13 is independently selected in each case from a hydrogen moiety, C1-4 alkyl, halo substituted C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl. C5-7 cycloalkenyl, C5-7 cycloalkenyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocyclyl or heterocyclyl-C1-4 alkyl alkyl, and in which each of these residues, excluding hydrogen, may be optionally substituted; each of Rd and Rd 'is independently selected from a hydrogen moiety, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl, and where each of these moieties, excluding hydrogen, may optionally be replaced; or Rd and Rd ', together with the nitrogen to which they are attached, form an optionally substituted 5 to 6 membered heterocyclic ring, wherein said ring optionally contains a heteroatom more selected from oxygen, sulfur or NR9'; Rb is a hydrogen moiety, C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-10 alkyl, aryl, aryl-C1-10 alkyl. heteroaryl, heteroaryl-C1-10 alkyl, heterocyclyl or heterocyclyl-C1-10 alkyl, where all these moieties, excluding hydrogen, may be optionally substituted; Rg is C1-10 alkyl, or aryl; m is 0 or an integer that has the value 1 or 2; s is an integer that has a value of 1, 2, 3 to 4; and t is an integer that has a value of 1, 2, 3 or 4; v is 0 or an integer that has the value 1 or 2; v 'is independently selected in each case from 0 or an integer having a value of 1 or 2; Z is independently selected from oxygen or sulfur; R10 and R20 are independently selected from hydrogen or C1-4 alkyl and R10 'is independently selected in each case from hydrogen or C1-4 alkyl; Single reactor process, in situ, to manufacture a compound